The information of senile plaques in the brain is characteristic of patients with Alzheimer's disease (AD). These plaques are composed mainly of dystrophic neurons, reactive microglia, and amyloid-beta (Abeta). Abeta is a proteolytic cleavage product of the amyloid-beta precursor protein (APP) and has been implicated in AD pathogenesis. Abeta may promote neuronal cell injury by at least two general pathways. First, Abeta may be cytotoxic to neurons themselves and second, Abeta can activate microglia which can cause neurodegeneration. Several lines of evidence implicate the transcription factor NF-kappaB as a potentially critical component in the development of AD. The APP promoter contains homologies to the kappaB consensus, Abeta can activate an HIVCAT reporter through kappaB sites, and several cytokines and other factors which activate APP expression can activate NF-kappaB. This evidence and the knowledge that microglia can be activated by Abeta as well as activated by Abeta as well as secrete Abeta, suggests a model where the activation of microglia and NF-kappaB is critical in the development of AD. An additional focus is to determine if Abeta regulates APP gene expression through an autoregulatory loop that requires NF-kappyB, which would lead to the chronic deposition of Abeta. Promoter deletion analysis, site-directed mutagenesis, transient transfections, EMSAs, and Western and Northern analyses will be used to elucidate the roles of NF-kappaB and Abeta in neurodegeneration and microglial activation. Results from these studies may be significant in developing therapeutic strategies targeting AD and other neurodegenerative diseases.